Aa
simvastatin+interferon, why is there anincreased responce?
http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000598#pbio-1000598-g004
Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis
quite complicated and studying various viruses, mainly dna viruses like hbv...the sum of it is for us: interferon+sim+vit d+alinia increase interferon response.this study explains why it happens on interferon+sim:
therapeutic Perspective
Several viruses including human CMV have been reported to be sensitive to statin administration [25],[26],[28]–[31]. Although the mechanism of action of most is not known, it has in some cases been correlated with a lower abundance of cholesterol in lipid rafts of cell membranes. A recognized potential complicating factor of using statins to specifically reduce cholesterol levels is that suppression of the proximal mevalonate arm also perturbs the synthesis of branch derivatives such as geranylgeraniol and farnesol involved in the protein farnesylation and prenylation pathways. In the case of HCV, the mechanisms of the inhibitory effects of the statins have been examined extensively and have been shown to relate to the prenylation of a host protein (FLB2) essential for viral replication [18],[57]. Recently a combination chemical screening study has been conducted to explore how the sterol and protein prenylation pathways work together to affect HCV in a replicon assay [32]. In agreement with those studies we also find reduced mCMV growth in siRNA knock-down experiments targeting enzymes in the isoprenod biosynthesis pathway. These studies indicate the importance of the geranylgeranylation to viral replication. Although, it is worth noting that the isoprenoid biosynthesis pathway is highly complicated with multiple branch points involving redundant enzymatic steps, sharing of subunits, and competing reactions. In our current study, we uncoupled the cholesterol synthesis pathway from non-steroidal modifications through targeted metabolic rescue and siRNA knock-down studies of mCMV and reveal an absolute requirement for the prenylation branch of the sterol pathway for mediating anti-viral effects. As further indicated from computational modeling work (unpublished data), targeting HMGCR is likely to have a broad range of non-specific effects on various efferent branch points of the pathway and thus may well not be ideal for anti-infective therapy. In addition, statins are also known to have a range of immune-modulatory activities by mechanisms yet to be fully characterized. In this context, it is worth noting that the activity of the type I interferons, especially IFNβ, have considerable overlap with many of the immune-related activities of statins [58]. Moreover, it is especially noteworthy that IFNβ treatment in patients has also been reported to have decreased plasma cholesterol levels [59],[60]. Since our studies uncover a molecular dependency of type 1 signaling, including a Tyk2 signaling component, this may provide an entirely new therapeutic pathway for lowering cholesterol. Moreover, our findings may have important implications for the development of broadly active new adjuvant strategies (e.g., the use of inhibitors of SREBP2 activity) to existing anti-infective therapies (e.g., antiviral drugs such as ganciclovir). On this basis we posit the principal of using metabolic modifiers, i.e. drugs that target metabolic pathways, of protective innate immunity as holding future promise for developing host-directed anti-viral therapies. Overall, this study supports the original concept [40],[41] of selectively targeting host pathways as an efficacious anti-infective strategy.
Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis
quite complicated and studying various viruses, mainly dna viruses like hbv...the sum of it is for us: interferon+sim+vit d+alinia increase interferon response.this study explains why it happens on interferon+sim:
therapeutic Perspective
Several viruses including human CMV have been reported to be sensitive to statin administration [25],[26],[28]–[31]. Although the mechanism of action of most is not known, it has in some cases been correlated with a lower abundance of cholesterol in lipid rafts of cell membranes. A recognized potential complicating factor of using statins to specifically reduce cholesterol levels is that suppression of the proximal mevalonate arm also perturbs the synthesis of branch derivatives such as geranylgeraniol and farnesol involved in the protein farnesylation and prenylation pathways. In the case of HCV, the mechanisms of the inhibitory effects of the statins have been examined extensively and have been shown to relate to the prenylation of a host protein (FLB2) essential for viral replication [18],[57]. Recently a combination chemical screening study has been conducted to explore how the sterol and protein prenylation pathways work together to affect HCV in a replicon assay [32]. In agreement with those studies we also find reduced mCMV growth in siRNA knock-down experiments targeting enzymes in the isoprenod biosynthesis pathway. These studies indicate the importance of the geranylgeranylation to viral replication. Although, it is worth noting that the isoprenoid biosynthesis pathway is highly complicated with multiple branch points involving redundant enzymatic steps, sharing of subunits, and competing reactions. In our current study, we uncoupled the cholesterol synthesis pathway from non-steroidal modifications through targeted metabolic rescue and siRNA knock-down studies of mCMV and reveal an absolute requirement for the prenylation branch of the sterol pathway for mediating anti-viral effects. As further indicated from computational modeling work (unpublished data), targeting HMGCR is likely to have a broad range of non-specific effects on various efferent branch points of the pathway and thus may well not be ideal for anti-infective therapy. In addition, statins are also known to have a range of immune-modulatory activities by mechanisms yet to be fully characterized. In this context, it is worth noting that the activity of the type I interferons, especially IFNβ, have considerable overlap with many of the immune-related activities of statins [58]. Moreover, it is especially noteworthy that IFNβ treatment in patients has also been reported to have decreased plasma cholesterol levels [59],[60]. Since our studies uncover a molecular dependency of type 1 signaling, including a Tyk2 signaling component, this may provide an entirely new therapeutic pathway for lowering cholesterol. Moreover, our findings may have important implications for the development of broadly active new adjuvant strategies (e.g., the use of inhibitors of SREBP2 activity) to existing anti-infective therapies (e.g., antiviral drugs such as ganciclovir). On this basis we posit the principal of using metabolic modifiers, i.e. drugs that target metabolic pathways, of protective innate immunity as holding future promise for developing host-directed anti-viral therapies. Overall, this study supports the original concept [40],[41] of selectively targeting host pathways as an efficacious anti-infective strategy.
Statins and the Risk of Hepatocellular Carcinoma in Patients With Hepatitis B Virus Infection
Yu-Tse Tsan, Chang-Hsing Lee, Jung-Der Wang and Pau-Chung Chen⇓
+ Author Affiliations
All authors, National Taiwan University College of Public Health; J.-D.W. and P.-C.C., National Taiwan University College of Medicine and Hospital, Taipei; Y.-T.T., Taichung Veterans General Hospital; Y.-T.T., Chung Shan Medical University, Taichung; C.-H.L., Ton Yen General Hospital, Hisn-Chu County; and J.-D.W., National Cheng Kung University College of Medicine, Tainan, Taiwan.
Corresponding author: Pau-Chung Chen, MD, PhD, Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, 17 Syujhou Rd, Taipei 10055, Taiwan; e-mail: ***@****.
Abstract
Purpose Statins have potential protective effects against cancers, but no studies have focused on patients with chronic hepatitis B virus (HBV) infection. The purpose of this study was to investigate the association between the use of statins in HBV-infected patients and the risk of hepatocellular carcinoma (HCC).
Patients and Methods We conducted a population-based cohort study from the Taiwan National Health Insurance Research Database. A total of 33,413 HBV-infected patients were included as the study cohort. Each patient was individually tracked from 1997 to 2008 to identify incident cases of HCC since 1999. Subsequent use of statin, other lipid-lowering agents, aspirin, and angiotensin-converting enzyme inhibitors was identified. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% CIs for the association between the use of statins and the occurrence of HCC in the HBV-infected cohort.
Results There were 1,021 HCCs in the HBV cohort during the follow-up period of 328,946 person-years; the overall incidence rate was 310.4 HCCs per 100,000 person-years. There was a dose-response relationship between statin use and the risk of HCC in the HBV cohort. The adjusted HRs were 0.66 (95% CI, 0.44 to 0.99), 0.41 (95% CI, 0.27 to 0.61), and 0.34 (95% CI, 0.18 to 0.67) for statin use of 28 to 90, 91 to 365, and more than 365 cumulative defined daily doses (cDDDs), respectively, relative to no statin use (< 28 cDDDs).
Conclusion Statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner. Further mechanistic research is needed.
Yu-Tse Tsan, Chang-Hsing Lee, Jung-Der Wang and Pau-Chung Chen⇓
+ Author Affiliations
All authors, National Taiwan University College of Public Health; J.-D.W. and P.-C.C., National Taiwan University College of Medicine and Hospital, Taipei; Y.-T.T., Taichung Veterans General Hospital; Y.-T.T., Chung Shan Medical University, Taichung; C.-H.L., Ton Yen General Hospital, Hisn-Chu County; and J.-D.W., National Cheng Kung University College of Medicine, Tainan, Taiwan.
Corresponding author: Pau-Chung Chen, MD, PhD, Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, 17 Syujhou Rd, Taipei 10055, Taiwan; e-mail: ***@****.
Abstract
Purpose Statins have potential protective effects against cancers, but no studies have focused on patients with chronic hepatitis B virus (HBV) infection. The purpose of this study was to investigate the association between the use of statins in HBV-infected patients and the risk of hepatocellular carcinoma (HCC).
Patients and Methods We conducted a population-based cohort study from the Taiwan National Health Insurance Research Database. A total of 33,413 HBV-infected patients were included as the study cohort. Each patient was individually tracked from 1997 to 2008 to identify incident cases of HCC since 1999. Subsequent use of statin, other lipid-lowering agents, aspirin, and angiotensin-converting enzyme inhibitors was identified. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% CIs for the association between the use of statins and the occurrence of HCC in the HBV-infected cohort.
Results There were 1,021 HCCs in the HBV cohort during the follow-up period of 328,946 person-years; the overall incidence rate was 310.4 HCCs per 100,000 person-years. There was a dose-response relationship between statin use and the risk of HCC in the HBV cohort. The adjusted HRs were 0.66 (95% CI, 0.44 to 0.99), 0.41 (95% CI, 0.27 to 0.61), and 0.34 (95% CI, 0.18 to 0.67) for statin use of 28 to 90, 91 to 365, and more than 365 cumulative defined daily doses (cDDDs), respectively, relative to no statin use (< 28 cDDDs).
Conclusion Statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner. Further mechanistic research is needed.
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